Orally administered drugs are provided to the patient in many dosage forms, including solid forms such as capsules, caplets or tablets and liquid forms such as solutions, syrups, emulsions or suspensions. Pharmaceutically active agents administered in solid dosage form are usually intended to be swallowed whole. The disagreeable taste of the drug is generally not of concern when formulating oral solid dosage forms, because the pharmaceutical's taste can be easily masked with an exterior coating.
Children, older persons, and many other persons including disabled or incapacitated patients often have trouble swallowing tablets or capsules. In these situations, it is desirable to provide the drug either in a chewable solid form or a liquid form. For many patients, including pediatric and geriatric patients, a liquid oral dosage form is preferred over a chewable dosage form. A liquid dosage form is especially preferred for this class of patients because of the ease with which it may be swallowed. Additionally, patients may be more inclined to comply with their medication instruction if the dosages are easier to ingest, particularly for products administered in large doses, requiring several tablets at a time.
Some liquid pharmaceutical compositions formulated for use by pediatric or geriatric patients are often prepared by grinding a tablet dosage form into a powder and mixing the powder with a diluent. Such a formulation may cause some of the drug to remain undissolved, thereby affecting the therapeutic dose of drug in the composition. In addition, the powder exposes the unpleasant tasting pharmaceutically active agent, which may result in a lack of compliance due to the unacceptable taste. It is readily understood that such compositions are impractical and may result in underdosing or poor compliance.
A common formulation problem associated with liquid pharmaceutical dosage forms (such as solutions (including syrups or suspensions) is masking the disagreeable taste that a pharmaceutically active agent may often manifest when administered in a liquid dosage form. Many active ingredients, such as antibiotics, possess a strong, unpleasant and bitter taste. Deferiprone particularly has an extremely bitter taste as discussed in the Merck Index. Prior attempts to provide acceptable and palatable liquid deferiprone formulations have been unsuccessful.
Pfertec Limited of London England had previously prepared a liquid deferiprone formulation which was never approved, but was sold as a research drug only to physicians for use in patients on a named patient basis. The taste was unbearably unpleasant. There was no disclosure of the details of the Pfertec liquid deferiprone composition, but taste comparisons, conducted by the applicant, revealed they had failed to produce a palatable product for commercial purposes.
The prior art has shown extensive use of one or a combination of different flavoring methodologies to mask the bitter taste of drugs. For example, a flavor can be selected that complements the taste of the preparation, or a flavor with a longer intensity and stronger taste than the drug can be used. High levels of sweetening agents are often used to overwhelm bitterness with sweetness. The taste buds may also be anesthetized by menthol or mint flavors. These approaches are generally not very effective in masking the taste of a bitter drug, and a flavoring system that works with one drug often does not apply to another drug.
The prior art also indicates that taste masking may be achieved by increasing the viscosity of liquid preparations. Various combinations of viscosity modifiers for taste masking exist in the patent literature. For example, U.S. Pat. No. 5,616,621 provides alleged taste masked liquid preparations by increasing the viscosity with a combination of polyethylene glycol and sodium carboxymethylcellulose; and U.S. Pat. No. 5,658,919 discloses alleged taste masking of an acetaminophen suspension using a suspending system consisting of xanthan gum and a mixture of cellulosic polymers. The increase in viscosity is assumed to limit the contact of the drug with the tongue, presumably by slowing down salivary water uptake into the viscous liquid medicament, which can lead to dilution and dissolution of the taste-offending ingested medication. This approach is only moderately successful in reducing bitterness especially at high drug loading. While bitterness may be reduced at the onset, bitter aftertaste becomes prominent after swallowing because thick preparations are more difficult to wash down thus leaving behind some residual viscous liquid medicament in the mouth after swallowing. This bitter aftertaste is more prominent with water intake due to the reduction in viscosity and dilution of the residual liquid medicament and subsequent dissolution of the drug in the mouth.
Several other approaches have been pursued to address the unpleasant taste of a drug in a liquid format. U.S. Pat. No. 5,730,997 illustrates the use of a hyperosmotic liquid using a sugar derivative and maltose syrup for taste masking. U.S. Pat. No. 5,154,926 claims reduction of the bitter taste of acetaminophen syrup by using a water-soluble macromolecule with a polyhydric alcohol and/or polymer of a polyhydric alcohol of MW 300-400. U.S. Pat. Nos. 5,763,449 and 5,962,461 teach the use of a combination of povidone, C3-C6 polyol and ammonium glycyrrhizinate for taste masking. EP application No. 1025858A1 discloses relief of bitterness of basic drugs by combining propylene glycol with povidone and/or copolyvidone.
In the case of developing a palatable formulation for a liquid deferiprone product, several approaches were used without success, resulting in a product not much more palatable than the Pfertec product. Thus a series of iterative steps were taken to overcome the difficulty experienced in developing a liquid formulation for deferiprone that has a palatable taste.
It is therefore a primary aspect of the invention to provide a palatable liquid deferiprone formulation using a taste masking composition directed specifically at the offending taste generated by deferiprone.
It is yet another object of this invention to provide a taste masked liquid deferiprone formulation wherein the taste masking composition comprises a taste masking effective amount of sucralose and optionally at least one flavouring agent.
Further and other objects of the invention will become apparent to one skilled in the art when reviewing the following summary of the invention and the more detailed description of the preferred embodiments contained herein.